PROJECT SUMMARY The goal of this proposal is to define the molecular and metabolic effects of fetal hypoxia on the development of fetal hepatic insulin resistance and activation of fetal hepatic glucose production rate (GPR). This is important because pregnancies complicated by placental ischemic diseases and specifically placental insufficiency induced intrauterine growth restriction (PI-IUGR) expose the fetus to hypoxia. We have shown that the fetal liver during PI-IUGR has increased hepatic GPR, which is resistant to suppression by insulin. While hepatic insulin resistance and increased GPR are likely vital adaptations in the PI-IUGR fetus, these events also are early key hallmarks of type 2 diabetes (T2DM), to which PI-IUGR offspring are more susceptible. The PI-IUGR fetus also has limited glucose oxidation capacity and decreased hepatic oxygen consumption, suggesting decreased mitochondrial substrate oxidation, which may re-direct carbon for GPR. Our goal is to understand the mechanisms for the early activation of hepatic glucose production in response to fetal hypoxia. The overall hypothesis of this proposal is that fetal hypoxia is the major driver of hepatic insulin resistance, increased hepatic glucose production, and decreased hepatic mitochondrial oxidation in the fetus. In Aim 1, we will test the role of fetal hypoxia on the development of hepatic insulin resistance, increased hepatic glucose production, and decreased hepatic mitochondrial oxidation. In Aim 2, we will determine whether chronic fetal hypoxia produces hepatic insulin resistance via increased nuclear FOXO1 and decreased AMPK activity resulting in increased PCK1 and PDK4 expression in the fetal liver. In Aim 3, we will determine the synergistic coordination between glucose production and mitochondrial oxidation in isolated hepatocytes. The results of our studies will allow us to determine the specific role of fetal hypoxia in the fetal liver on the activation of hepatic GPR and development of hepatic insulin resistance. We also will identify the molecular and metabolic pathways involved in GPR that are regulated by hypoxia in the fetal liver. Our studies also will differentiate hypoxia from relative hypoglycemia as a principal cause of fetal hepatic GPR. The fetal liver is one of the most severely affected organs by PI-IUGR and the only fetal organ to demonstrate insulin resistance, a hallmark of later life T2DM. Defining fetal hypoxia as an early driving factor and the pathophysiological adaptations induced by hypoxia may represent the key to understanding how fetal hypoxia programs the fetal liver to produce glucose, establishing a direct risk for developing T2DM in later life.